Portable coagulation  monitoring device for assessing coagulation response

ABSTRACT

A device, system and method is disclosed in which small volume blood samples are subjected to shear forces and shear stresses between two parallel planar surfaces to which linear motion trajectories are imparted. The formation of clots or coagulation of the sample is measured from dynamic mechanical coupling which occurs between the two parallel planar surfaces. Detection of the coagulation response can be achieved through optical probing or by measurement of physical effects of the blood sample binding to the planar surfaces, and restricting movement thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.12/971,013 filed Dec. 17, 2010, now U.S. Pat. No. 8,450,078 issued May28, 2013, entitled “Portable Coagulation Monitoring Device and Method ofAssessing Coagulation Response”, the application of which claimspriority to U.S. Provisional Application Ser. No. 61/287,780 filed Dec.18, 2009, entitled “Portable Coagulation Monitoring Device, System andMethod of Use”; the disclosures of which are expressly incorporated byreference herein in their entireties.

FIELD OF THE INVENTION

The invention relates to a device, and method which allows rapidassessment of coagulation response. More particularly, the inventionrelates to such a device and method which provides extensive and complexinformation on coagulation response, including platelet function andfibrin polymerization to allow selection of appropriate treatmentprotocols, in particular for trauma induced coagulopathies but also forthe diagnosis of hereditary or acquired abnormalities of coagulation,such as von Willebrand disease or hemophilias.

BACKGROUND OF THE INVENTION

The process by which the body prevents blood loss is referred to ascoagulation. Coagulation involves the formation of a blood clot(thrombus) that prevents further blood loss from damaged tissues, bloodvessels or organs. This is a complicated process with a cellular systemcomprised of cells called platelets that circulate in the blood andserve to form a platelet plug over damaged vessels and a second systembased upon the actions of multiple proteins (called clotting factors)that act in concert to produce a fibrin clot. These two systems work inconcert to form a clot and disorders in either system can yielddisorders that cause either too much or too little clotting.

Platelets serve three primary functions: (1) sticking to the injuredblood vessel (a phenomenon called platelet adherence), (2) attaching toother platelets to enlarge the forming plug (a phenomenon calledplatelet aggregation), and (3) providing support for the processes ofthe coagulation cascade (molecules on the surface of platelets greatlyaccelerate several key reactions)

When a break in a blood vessel occurs, substances are exposed thatnormally are not in direct contact with the blood flow. These substances(primarily collagen and attached multimeric von Willibrand factor) allowthe platelets to adhere to the broken surface. Once a platelet adheresto the surface, it releases chemicals that attract additional plateletsto the damaged area, referred to as platelet aggregation. These twoprocesses are the first responses to stop bleeding. The protein basedsystem (the coagulation cascade) serves to stabilize the plug that hasformed and further seal up the wound.

The support role of the platelet to the coagulation cascade is provided,in part, by one of the components on the outside of a platelet, calledphospholipids, which are required for many of the reactions in theclotting cascade. The goal of the cascade is to form fibrin, which willform a mesh within the platelet aggregate to stabilize the clot. All ofthe factors have an inactive and active form. Once activated, the factorwill serve to activate the next factor in the sequence until fibrin isformed. The coagulation cascade takes place at the site of a break in ablood vessel that has the platelet aggregate. Fibrin forms a mesh that,in concert with the platelets, plugs the break in the vessel wall. Thefibrin mesh is then further stabilized by additional factors whichcross-linkup the clot (much like forming an intricate network ofreinforced strands of fibrin).

In the case of trauma induced bleeding, it is important to understandvery quickly the clotting response of a particular individual in orderto apply appropriate therapy to treat bleeding and ensure that thetrauma is dealt with appropriately. Defective platelet functions, bothprimary (adhesive, von Willibrand factor interaction) and secondary(fibrin polymer organization and polymerization, integrin function) arerecognized as a particularly important contributor in prolongednon-compressible bleeding. The development of hemostatic disorders intrauma patients, and associated progression in hemorrhagic and othershock states, can be due to different factors and thus require differenttherapies.

Currently, thromboelastography (TEG) is the accepted clinical standardfor testing the efficiency of whole blood coagulation. For purposes ofthis disclosure, it should be noted that by “whole blood” is meant amixture of whole blood with one or more substances, a fraction of wholeblood containing one or more of the constituents of whole blood, afraction of whole blood mixed with one or more non-blood substances, ora purified blood constituent, such as blood platelets or serum, areconstituted blood preparation, a modified blood sample, or a bloodsubstitute.

A TEG system was first developed in Germany in 1948 and has beenincrementally improved since then. However, its principle of operationremains the same.

Traditional TEG requires a relatively large sample of blood, i.e., about0.36 ml in a small cup. A pin is inserted into the blood and is rotatedin a sinusoidal oscillation through a small angle at a low frequency.The device measures coupling of motion through rotation over time. Itdoes not measure platelet adhesion, only polymerization of fibrin, anddoes not allow for mechanical activation of the coagulation responsethrough shear forces. Thus, the information obtained from a TEG analysisfalls far short of our current understanding of coagulation response,and requires excessive amounts of time which could result ininappropriate treatment for trauma being applied, leading to adverseresults to a patient, possibly even death.

Another device generally known as the PFA-100 attempts to mimic a bloodvessel by forcing blood flow through a narrow channel leading to afilter which has an aperture therein. The device measures the time forthe aperture to clog and is essentially indicative of platelet functionresponse which results in clogging. The time of closure of the apertureindirectly provides an indication of clotting due to platelet response.The use of such devices as TEG and the PFA-100 requires intensivelaboratory training and upkeep, and they are not easily used in thefield.

Accordingly, it is desirable to provide a portable coagulationmonitoring device for diagnosis of trauma-related coagulopathies in thefield, which yields rapid results, including extensive information aboutthe complex mechanisms involved in coagulation, from a small sample ofblood. More specifically, it is important to provide such a device whichcan be used by first responders under conditions encountered in thefield, providing real time information, which allows for immediatetreatment of a hemorrhaging event, as compared to prior art systems anddevices which could result in delays of 45 minutes or more during whatis considered an important initial time period for critical care to beapplied and which use non-anticoagulated blood samples that do not haveto be treated with activators and initiators as surrogates for the truecoagulation process.

SUMMARY OF THE INVENTION

In one aspect, the invention relates to a device for measuringcoagulation response in a native, non-anticoagulated blood sample. Thedevice includes two members or plates each having surfaces facing eachother, and spaced an amount sufficient to allow a relatively smallsample of blood to contact both surfaces at the same time without an airspace between.

The plates are movable relative to each other in a parallel and lineardirection, and the spacing is such that the components of blood caninitiate coagulation or adherence to each of the surfaces. A drivemechanism is connected to either one or both of the members for linearlymoving one or the other relative to each other when a blood sample is incontact with their surfaces. An optical detection sensor system isprovided for detecting interaction of light with a blood sample locatedbetween the two members, with the interaction of light and detectionthereof providing an indication of coagulation response of the bloodsample. More specifically, with appropriate positioning of light sourceand detectors, over time and in accordance with the variation of themovement of the members to generate a particular shear rate, informationabout both platelet response, fibrin response and other responses of theblood components during coagulation can be obtained.

More specifically, the device allows for the measurement of coagulationresponse based on the knowledge that the biophysical response of blooddepends in part on the relative shear rate between the blood andsurfaces with which it is in contact. More specifically, the higher theshear rate, the greater the platelet response so that the platelets thenstick to the surfaces of the plates, and thereby trigger the fibrinpolymerization and couple the motion of the two plates when only one isdriven by the motors. More specifically, it is recognized that inhemorrhaging events platelets need to react quickly so the use of a highshear rate for a short time period can allow accurate assessment ofplatelet response for these conditions. Thereafter, lower shear ratescan be employed in terms of relative movements of the plates or memberswith respect to each other, to obtain an accurate assessment of fibrinresponse, or at an intermediate shear rate, both fibrin and plateletresponse.

“Shear” here is defined as the acceleration force felt by a particle inthe moving bulk flow of fluid (blood) at the interface with thestationary solid (face of the glass plates). The shear “rate” is thedifferential of velocities felt on different aspects of the particle'scross-sectional area and is dependant on the particle's distance fromthe stationary surface.

In a preferred aspect, the first member and second members are platesmaking up a blood sample collection cartridge which is removable fromthe device. In the case that one or both plates are moved with respectto each other, the device is programmed for moving the plates atdifferent speeds relative to each other for detecting differentmechanisms involved in a coagulation response of a blood sample, aspreviously discussed with respect to shear.

The optical detection system is adapted for detecting binding of theblood sample to the surfaces to couple the motion of the plates relativeto each other as an indication of platelet response during coagulation.In addition, the system can also probe fibrin response.

Other features and details of the device are described in the detaileddiscussion which follows, the Appendices hereto, and in the appendedclaims in which the invention is described in a nonlimiting manner.

In an alternative aspect there is provided a method of measuringcoagulation response in blood sample. A sample droplet of blood isplaced between and in contact with facing surfaces of oppositelydisposed plates. At least one or both plates are moved linearly withrespect to the other at a predetermined rate. The coagulation responseof the droplet is optically detected.

To detect two different types of coagulation response, the plates can bemoved relative to each other at a first speed and a response opticallydetected, and thereafter moved at a second speed which is slower thanthe first speed and a second response optically detected, typicallyfibrin polymerization. In addition, in the case where only one plate ismoved, it should be appreciated that the visco-elastic response of theblood sample on the surfaces of both plates can cause the movement ofthe first plate to induce movement of the second plate (“coupledmotion”), which can be measured as indicative of visco-elastic responseof the blood, ultimately leading to conclusions which may be inferredrelative to coagulation response. Moreover, by moving the plates atdifferent speeds over time, changes in the visco-elastic state of theblood sample may be measured as a clot is formed, which is alsoindicative of coagulation response.

Optical detection may be done by transmitting light into the sampledroplet, and detecting at least one of transmission, reflection andrefraction of the light through the sample droplet at respective lightdetectors. Analog signals may be generated from the detectionrepresentative of coagulation properties of the blood in the sampledroplet. The plates are preferably made of glass, more specificallytransparent glass, to allow light transmission of 90% or more of theincident light intensity.

These and other advantages and features that characterize the inventionare set forth in the claims annexed hereto and forming a further parthereof. However, for a better understanding of the invention, and of theadvantages and objectives attained through its use, reference should bemade to the Drawings, and to the accompanying descriptive matter,including Appendices I, II, III, and IV which are specificallyincorporated in their entirety by reference herein, in which there aredescribed exemplary embodiments of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic diagram illustrating various components making upthe device and system in accordance with the invention.

FIG. 2 is a schematic diagram of a sample cassette in which a sampledroplet may be loaded, and which may be employed in an exemplaryembodiment of the portable coagulation monitor in accordance with theinvention, for example, as shown in FIG. 1.

FIG. 3 in a schematic diagram illustrating relative movement of twoplates in contact with blood to cause shear and initiate clottINGresponse

FIG. 4 is a perspective view of an embodiment of the device of theinvention.

FIG. 5 is an exploded view of an embodiment of the device of theinvention.

DETAILED DESCRIPTION OF THE INVENTION

FIG. 1 illustrates in schematic form an exemplary portable coagulationmonitor or assay device 11 for diagnosis of trauma or other relatedcoagulopathies in which it is important to assess coagulation responseto optimize treatment, for example, in critical field situations whereinthe first hour is critical in terms of preventing long-term debilitatingevents or even death.

The device is housed in an impact resistant housing 13 which has all thecomponents housed thereon in a conventional manner.

At least one and preferably a pair of linear voice coil actuator motors15 and 17 are provided for driving movement of sample plates in aremovable blood sample cassette which is illustrated in greater detailin FIG. 2. While the motors 15 and 17 and removable blood samplecassette 19 have been described briefly, the remaining components arediscussed generally with reference to the drawings in a clockwise mannerbeginning with the data card port 21 in the upper left-hand corner ofthe device.

The data card port 21 is useful for receiving an FD card or any memorymodule, including data on the module for calibrating the device 11,and/or for removing data from the device 11 for input into anothersystem in which the data can be analyzed. A USB port 23 allows fordirect interface with a computer, for example, under the control of aphysician for a more complex analysis.

Microcontroller 25 operates with EEPROM 26 and handles data from the USBport and the data card port 21 and can provide control for a userinterface (not shown) such as an LCD display which provides initiallyacquired data and analysis thereof to a user using the device. Linearvoice coil actuator motors 15 and 17, and the removable blood samplecassette 19 have been briefly described and will be discussed in greaterdetail hereinafter.

A wireless link 27, such as for transmitting data in the RF or IRspectrum, is also provided, and provides an additional means forcommunicating data and programming to and from the device. Opticaldisplacement sensors 29 and 31 detect where the linear voice coilactuator motors 15 and 17 are located and control the limits of movementthereof. The digital synthesizer module 33 serves to control operationof the motors 15 and 17 through motor drivers 35 by generating thenecessary waveforms to drive the voice coil actuator motors 15 and 17.

The ADC module 37 is an analog to digital converter which obtains datafrom the optical or physical measurements conducted on a sample in theremovable blood cassette 19, converts the data into digital form andsupplies it to microcontroller 39 which manages the data obtained toprovide useful results to a user of the device.

A 3-axis accelerometer 41 is a conventional device which takes intoaccount outside effects and vibrations on the device 11, and serves tocancel the effects of these vibrations on any data collected as a resultof analysis of a sample.

The removable blood sample cassette 19 is shown in FIG. 2 in schematicform and includes an upper sample plate 101 and a lower sample plate 103between which can be deposited a sample droplet of blood. Linkages 105to the voice coil actuator motors on the device are provided, which areconnected to an upper linear compliant mechanism 107 and a lower linearcompliant mechanism 109 which serve to drive movement of the upper andlower plates respectively. Optical sensors 111 are provided in positionrelative to the sample plates for detecting light being projected from,for example, a laser or other light source (not shown), through and intoa sample between the plates. The light can then be detected as lighttransmitted through the sample, reflected, refracted or otherwisemodified in the path through the sample, and detected by optical sensors111 to obtain information about the coagulation properties of the bloodsample.

A power link 113 serves for connection to a power supply such as, forexample, batteries or other form of power. A data link 115 can also beprovided to allow data collected from the sample and stored on an EEPROM117 to be downloaded from the device. In this context, it will beappreciated by those of ordinary skill in the art that the data link 115and EEPROM 117, when the cassette 19 is received in the device 11, canbe connected to the various electronic components within the device 11for having data uploaded and downloaded thereto.

As may also be appreciated by those of ordinary skill in the art, FIG. 3further illustrates the operation of the device in accordance with theinvention and with parallel plates, typically having a small gap ofabout 50 to about 250 μm between the parallel plates. They slide pasteach other with controlled velocity to create a shear stress between theplates which is represented as T=μV/D where T equals shear stress,μ=viscosity, V=V1+V2, wherein V is equal to the relative linear velocityof the plates, and D=gap between the plates.

FIG. 4 further illustrates in assembly view, a device 11 in accordancewith the invention showing various components thereof. As may beappreciated from FIG. 4, the device is pocket-sized, preferably withoverall dimensions similar to an iPhone, of about 12 cm by about 6 cm byabout 2 cm. The device 11 is ruggedized with an internal accelerometercompensating for impacts and vibration. As designed it is versatile andcan measure platelet and fibrin clotting over a wide dynamic range ofshear. Yet still further, the device 11 can operate on USB hub power asa peripheral device with components which are readily manufactured andassembled. Typically, biophysical resolution is less than about 2μdisplacement, and the device 11 allows for a wide range of shearstresses and complete optical access.

As further illustrated in the exploded view of FIG. 5, the device 11preferably is made of a monolithic CNC-machined housing, of materialssuch as Acetal, 6Al-4V Ti, 2024 Al. A bottom sample window 203cooperates with a top sample window 205 and they are moved bydisplacement sensor arms 207. A monolithic compliant four-bar mechanism209 made typically of aluminum is associated with the displacementsensor arms 207. Motor assemblies 211, typically a VCA motor coilassembly, serves to move the various components and is associated with amagnet assembly 213, typically made of rare earth. Optical sensor arrays215 serve to interrogate and measure the clotting response. The sensorarrays 215 are typically infra-red differential displacement sensorarrays.

Preferably in the device, the first and second surfaces of the plates101 and 103 have, at least, been coated with textures, substances orother materials to induce, slow or otherwise modify the coagulationprocess so as to select for or against specific aspects of coagulationof the sample for diagnostic or other purposes. Modification to thesurfaces can include those that enhance platelet or blood proteinbinding reactivity or activation. Similarly, such modification canreduce platelet or blood protein binding reactivity, or activation aswill become more clearly evident from the following detailed discussionof such treatments or coatings.

The device is capable of analyzing blood rheology and coagulation offresh whole blood or some fraction thereof without the need to addexternal reagents, such as tissue factor, kaolin, initiator, citrate andothers. Such substances and others may electively be added for detailedanalytical reasons, but in the most desired embodiment of the device,they are not necessary.

In accordance with the assembly, the device 11, is configured formeasuring in real time or with minimal delay the dynamic balance betweenpro and anti thrombotic hemostatic status by sequential samples from thesame person or animal. In a more preferred aspect, the motors 15 and 17are linear voice coil actuator motors, but can be any other type ofdevice capable of driving linear motion.

In one embodiment, detection of coagulation is done optically bymeasuring mechanical interaction between the first and second surfacesof the plates 101 and 103 resulting from changes in the viscosity of thesample fluid and binding to the plate surfaces. In a preferred aspect,the relative motions between the two plates 101 and 103 is controlled togenerate arbitrarily selected wave forms to induce desired fluid shearrates at selected amplitudes, frequency, duration, and sequence suchthat the device is enabled to emulate fluid shear as desired over a verybroad range, from DC (zero shear) to shear rates that would cause fluidcavitation and subsequent destruction of the cellular components of thesample, and continuously including all points in the shear rate spectrumbetween these two points.

More specifically, the shear rate is controlled in a sequence of valuesto generate specific protocols or plate motion paradigms for targeteddiagnostic or analytic objectives, such as rapid initiation of primarycoagulation, destructive or non-destructive viscoelastic evaluation ofearly, mid-phase, or late-phase clotting, emulation of clinicallyaccepted or otherwise recognized shear rate protocols for comparisonwith other commercial or experimental devices, or validation testingagainst known standards. While light can be used for optical detectionit is clear that the full electromagnetic spectrum of waves can be usedto generate analog signals representative of coagulation properties ofthe sample droplet for both primary and secondary coagulationmechanisms.

It should be noted that when the term “blood sample” is used herein, itis intended to mean whole blood, a mixture of whole blood with one ormore substances, a fraction of whole blood containing one or more of theconstituents of whole blood, a fraction of whole blood mixed with one ormore non-blood substances, or a purified blood constituent, such asblood platelets or serum, a reconstituted blood preparation, a modifiedblood sample, or a blood substitute.

In a specific embodiment, interchangeable sample cassettes 19 can beemployed, each one serving a different analytical and maintenance orcalibration function. One cassette 19 can be for regular calibration andvalidation of the device 11. Alternatively, such a disposable andreplaceable cassette 19 can serve to calibrate the device 11, receivethe blood sample, hold the blood sample, allow different sample chambergeometries for different test protocols, maintain sample the viabilityduring a test, serve for safe removal of the sample for storage such afreezing, freeze drying, etc., or for sample disposal without exposureto the blood sample. In one embodiment, the cassette 19 allows forcollection of the blood sample by means of simple capillary actioneliminating the need to use sample extraction and metering devices.

As will be appreciated by those of ordinary skill in the art, thecassettes 19 may be manufactured for different tests and applicationswith different sample plate spacings, different surface chemical andoptical properties, and similar variations for analysis and validationtesting.

The cassette 19 may contain optical interrogation electronics allowingdetection of blood status, type, pH, oxygenation, metabolites, toxins,or other measures detectable by optical means. The device 11 is suchthat through its electronics it can be interfaced with other laboratorysystems such as microscopes, etc. The plates 101 and 103 are preferablyoptically clear to allow optical signals to pass through the bloodsample allowing direct optical visualization of a portion or all of theblood sample between the planar surfaces. This allows transmission,reflection, internal reflection, selective absorption, polarization oroptical rotation, frustrated internal reflection (either partial ortotal), and conduction of laser beams or other light surfaces.

As already noted, the cassette 19 may contain a non-volatile permanentmemory storage device such as EEPROM 117, for containing initial datathat identifies the cassette, lot, manufacture date, and details ofconstruction, as well as allowing for storage of key data such asuser-defined sample identification information, test initiation time,test duration, and specified test output data and results, to bepermanently stored with each sample until destroyed.

The cassettes 19 may contain additional fluids or other materials suchas additives, preservatives, sealing or barrier agents, and other likeagents which can be added to or layered on top of the blood samplebefore, during, or after testing. In one embodiment not specificallyshown in the drawings, instead of linear motion, rotary motion can beused to induce shear in addition to or as a replacement for lineardisplacement previously discussed.

As constructed, the device 11 is capable of delivering mechanical shearto the blood sample over a wide dynamic range of mechanicaloscillations, including 0.0001 Hz to 1000 Hz employing a digitalsynthesizer 33 previously disclosed, typically a dual channelsynthesizer, with the ability to generate regular periodic waveformssuch as sine waves, triangle waves, square waves of varying duty cycle,frequency, and amplitude, plus the ability to generate arbitrarywaveforms with rapid changes in all parameters, such as slew rate,amplitude, etc., or which may also hold steady (DC) mechanicaldisplacements of either one or both of the planar surfaces. The motors15 and 17 may be driven by drivers 35 in a manner where either one orboth drive mechanisms are coupled with the motors 15 and 17, and can beemployed simultaneously to effect linear motion, or where either may beemployed as a single or in concert with the other mechanism serving as aprecision sensor for mechanical displacement. In such a system,mechanical features are incorporated such as 4-bar of multi-barmonolithic compliant mechanisms, to eliminate mechanical hysteresis fromthe use of sliding or rolling bearing surfaces other than thoseassociated with the blood sample itself.

Data analysis and reduction software may be incorporated into the deviceelectronics to allow the resulting measured parameters of bloodcoagulation to be stored for later retrieval, transferred to a computeror other device for display, storage, or analysis, displayedgraphically, displayed in numerical form with physical units, ordisplayed in icon or symbolic form to indicate a specific diagnosis,clinical indication, or parametric change of clinical significance. Thesoftware will allow the resulting data to be represented in such a wayto allow the user to compare the results directly with similar oranalogous results that would be expected from other devices with similarfunctions, or to display the data in such a way to render comparisonwith accepted standard values or ranges for coagulation parameters. Inthis context, it is noted that a user interface (not shown) isimplemented with the device such as a LCD user interface.

The device 11 employs plates 101 and 103 motion protocols coupled withdata analysis and data reduction software to enable the directassessment of, for example, platelet function, function of thecoagulation cascade, red blood cell (RBC) rheology, RBC aggregation, theeffects of pro- or anti-coagulation agents, fibrinolysis, and othercharacteristics of blood coagulation. The device 11, with appropriateuser requirements and user interfaces may be classified as “simple”(CLIA “waived” classification) to permit use in-home and by unskilledusers. The disposable cassette is configured for collecting and holdingthe blood sample through simple unskilled collection of the fluid samplewithout requiring the use of any measuring pipette, syringe, or othermetering device for blood sample collection. The cassette 19 allows safehandling, storage, retrieval, and disposal of the collected blood sampleand may be manufactured to allow adjustment of the surface area andspacing between the plates to allow the use of very small volumes ofblood, typically on the order of less than about 1 mL.

The device 11 and cassette 19 allows optical microscopic inspection ofmost or all of the sample volume before, during, or after coagulometricanalysis, using both standard and inverted microscopic arrangements. Thedevice 11 can be employed to diagnose and quantify diseases andderangements of blood coagulation, including but not limited to induced,acquired, and congenital conditions such as trauma-inducedcoagulopathies (TIC), von Willebrand Disease (vWD), coagulation factorconsumption, platelet consumption, thrombasthenia, platelet metabolicexhaustion, hemodilution, over-activation of protein C, S, andfibrinolytic pathways, altered RBC rheology, and improperly administeredcoagulation modulating therapeutics, and other diseases and conditionsof blood coagulation.

Yet still further, the device 11 can rapidly assess coagulopathies inthe field in a period of time less than 15 minutes, and preferably lessthan 4 minutes, at the site of an injury or trauma, during transport, orat any other time during the course of rescue, first response,treatment, surgical intervention, or recovery. Use of feedback andfeed-forward technology serves to stabilize the blood sample to resistthe effects of external mechanical noise, vibration, and shock fromimpact. Testing the time course of changes in both primary and secondarycoagulation during the early phase of medical response to trauma andblood loss can be effected. Similarly, intra-surgical testing of primaryand secondary coagulation, and changes to these mechanisms during thecourse of surgery can be accomplished.

The device 11 can be used for rapid in-vitro screening of bioactivecompounds intended to affect the mechanisms of primary or secondarycoagulation. It can also be used for guidance of clinical treatment ofdiseases of the mechanisms of primary or secondary coagulation.

Similarly, the device 11 and cassette 19 may be modified for use in themeasurement of the rheological properties of other bodily substances ofclinical and research interest, such as pulmonary mucous, for the studyof and clinical guidance of the treatment of cystic fibrosis, forexample, such applications requiring a specially-designed cassette(disposable) and specialized test protocols and firmware, or for use inthe study of new and novel fluids with variable rheology.

The device 11 employs opto-electronic and wireless means to allow morethan one device to be employed simultaneously, or with multiple samples,each with different test initiation times and different test durationsor different sample chamber test protocols, to provide a rich set ofcoagulation data to a central computer or data collection and displaydevice. This allows that many samples can be monitored simultaneously totrack dynamic changes in the coagulation status of blood from anindividual during surgery or recovery, or during transport or treatmentin the field.

As previously discussed, certain embodiments of the invention may takethe form of adding coatings to the plates 101 and 105, typically glassplates, on the surfaces that come into contact with the blood sample.These coatings may be of a character to promote platelet adherence andactivation, such as collagen, more specifically type IV collagen, ofhuman or bovine origin. Likewise, the coating may be derived from theextracellular matrix (ECM) of cultured fibroblasts, or from culturedendothelium, or derived from the natural subendothelial tissue of livingblood vessels of human or animal origin. Particular molecular componentsof the matrix, such as vitronectin or fibronectin may comprise thecoating or be an enriched feature of the matrix to enhance the adhesionproperties. The coating may also be of a synthetic nature to promoteplatelet adherence and/or activation, such as polyamides orpolyglucosamines, more specifically β-N-acetyl polyglucosamine ofnatural or synthetic origin. Other embodiments may incorporate coatingson the plates 101 and 105 to modulate platelet function, such asmaterials capable of releasing activators of platelet function, e.g.,adenosine diphosphate or epinephrine, or inhibitors of platelet functionsuch as prostaglandins, e.g., prostacyclin or prostaglandin E-1.

Another embodiment of the invention may take the form of adding coatingsto the plates 101 and 105 that promote, initiate, or modulate theprocess of coagulation and fibrin polymerization. These coatings maytake the form of materials capable of releasing micronized silica, orkaolin, or tissue factor (natural or recombinant), or other such agentswhich are known to promote steps in the coagulation cascade. Thecoatings may also be of a nature to reverse anticoagulants that may bepresent in the blood sample, such as a material capable of releasing theenzyme heparinase to remove heparin, or mineralized calcium to reversecitrate. These coatings may be preferred for testing of blood frompatients that do not have sufficient platelet count or function to beable to initiate coagulation by the shear-induced mechanism of plateletactivation. For the same reason, the coatings may incorporate a sourceof phospholipids, either of natural or synthetic origin, or containpartial or whole thromboplastins to mimic the agents used in standardclinical coagulation tests such as the prothrombin time (PT) or partialthromboplastin time (PTT).

In yet another embodiment of the invention, coatings may be added to theplates that inhibit or modulate or reverse the effects ofhyperfibrinolysis in the blood sample, such as materials capable ofreleasing epsilon amino caproic acid (EACA), or trans-examic acid, oraprotinin, or other antiplasmin compounds or chemicals that affect theaction of the enzyme plasmin. These coatings may be preferred fortesting of blood from patients in a severe state of hyperfibrinolysisthat obfuscates the ability to extract other useful information on thecoagulation/hemostasis system components in the sample (and thus thepatient) unless the immediate effects of plasmin in the test system areablated. Likewise, the coatings may contain buffering compounds ofacidic or basic nature to adjust the blood sample pH to the optimaldesired level of between pH 7.2 to 7.4 or other specified level to avoidloss of information when the sample is overly acidotic or basic due tosevere conditions in the patient. These buffering compounds may take theform of released salts or amino acids or other zwitterionic polymericsoluble compounds biocompatible with blood for the purpose of producingand maintaining the desired pH.

These and other coatings to be added to the plates 101 and 105 of theinstant invention generally do not alter the geometry of the bloodsample space between the plates 101 and 105, or the motion and controlof the plates 101 and 105 by the motorized mechanism, beyond thecapacity of the system to be adjusted to maintain the required gapwithin specifications. For that reason, the preferred methods ofmanufacturing these coatings on the glass plates may include use ofelectrostatic charging and deposition of the desired materials directlyin contact with the glass members, or by layering of thin molecularhydrogels and carrier emulsions containing the desired agents in areleasable form suitable for activation immediately when contacted bythe blood sample.

The specified coatings may be comprised of single agents for a singularpurpose, or may be a combination mixture of several or more of thespecified coatings for multiple supporting purposes. One embodiment maybe comprised of having different coatings on the two surfaces, one ofone type and the other of a different type or at different density ormodification of the similar coating on the opposing member. In a furtherembodiment one or more coatings may be applied at differing densities orconcentration in differing areas of one or both surfaces, or withlinear, radial, or other gradients of density of coating on one or bothsurfaces. The pattern or gradient for each coating type may differ fromthat of other surface coating treatments on the same or opposingsurfaces. While in one exemplary embodiment the surfaces are glass, theymay be of any other material capable of accepting the coatings thereon,and of functioning in the manner intended, as will be evident to thoseof ordinary skill.

While the present invention has been illustrated by a description ofvarious embodiments and while these embodiments have been described inconsiderable detail, it is not the intention of the Applicants torestrict, or in any way limit the scope of the appended claims to suchdetail. The invention in its broader aspects is therefore not limited tothe specific details, representative devices and methods, andillustrative example shown and described. Accordingly, departures may bemade from such details without departing from the spirit or scope of theApplicants' general inventive concept of monitoring global hemostasisfunction in a portable device employing shear-induced activation ofplatelets and the full spectrum of response of blood coagulation.

What is claimed is:
 1. A device for measuring coagulation response in ablood sample, comprising: a first member having a first surface, and asecond member having a second surface, said first member positioned forhaving said first surface facing said second surface of said secondmember with sufficient space to allow a sample droplet of blood tocontact said first surface and said second surface and initiatecoagulation, and said first member and second member being linearlymovable relative to each other; a drive mechanism connected to at leastone of said first member and said second member for linearly moving saidfirst member and said second member relative to each other in parallelwhen a blood sample is in contact with said first surface and saidsecond surface, wherein the drive mechanism comprises at least onemotor; and an optical detection sensor system for detecting interactionof light with a blood sample located between said first member andsecond member, as an indication of coagulation response of said bloodsample; wherein the device further comprises at least onemicrocontroller for controlling operation of said drive mechanism andoptical detection sensor system.
 2. The device of claim 1, wherein saidfirst member and second member make up a blood sample collectioncartridge which is removable from said device.
 3. The device of claim 2,wherein said blood sample collection cartridge further comprises amemory device on said cartridge for storing data relating to a bloodsample tested.
 4. The device of claim 1, wherein the drive mechanism isprogrammed for moving the first member and second member at differentspeeds relative to each other for detecting different mechanismsinvolved in a coagulation response of a blood sample.
 5. The device ofclaim 1, wherein said optical detector sensor system is adapted fordetecting binding of the blood sample to the first surface and thesecond surface as an indication of platelet response during coagulation.6. The device of claim 1 wherein the said first and second surfaces (1and 2) have at least one been treated to induce, slow, or modify thecoagulation process for selecting in favor of or against specificaspects of coagulation of the sample for diagnostic or for otherpurposes.
 7. The device of claim 6, wherein said treatment of thesurfaces enhances platelet or blood protein binding, reactivity, oractivation.
 8. The device of claim 6, wherein said treatment of thesurfaces reduces platelet or blood protein binding, reactivity, oractivation.
 9. The device of claim 1, further comprising at least onedisplacement sensor for detecting and controlling the amount of relativemovement between said first member and said second member.
 10. Thedevice of claim 1, further comprising a connection interface module forconnecting and communicating between the device and an external system.11. The device of claim 1, wherein said drive mechanism comprises adevice capable of driving linear motion.
 12. The device of claim 1,further comprising an analog to digital converter connected to opticaldetection sensor system for converting analog signals indicative ofcoagulation response of a blood sample into digital signals for storagethereof.